rs12146610

Positions:

• chr11-103117775-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001377.3(DYNC2H1):​c.911A>T​(p.Gln304Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0596 in 1,613,268 control chromosomes in the GnomAD database, including 3,207 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.045 (211 hom., cov: 32)
  • Exomes 𝑓: 0.061 (2996 hom.)
• Consequence: DYNC2H1 NM_001377.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 8.88

Genes affected

DYNC2H1 (HGNC:2962): (dynein cytoplasmic 2 heavy chain 1) This gene encodes a large cytoplasmic dynein protein that is involved in retrograde transport in the cilium and has a role in intraflagellar transport, a process required for ciliary/flagellar assembly. Mutations in this gene cause a heterogeneous spectrum of conditions related to altered primary cilium function and often involve polydactyly, abnormal skeletogenesis, and polycystic kidneys. Alternative splicing results in multiple transcript variants encoding distinct proteins. [provided by RefSeq, Jan 2010]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002502948).
• BP6: Variant 11-103117775-A-T is Benign according to our data. Variant chr11-103117775-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 302005.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-103117775-A-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.062 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2	c.911A>T	p.Gln304Leu	missense_variant	6/90	ENST00000650373.2	NP_001073932.1
DYNC2H1	NM_001377.3	c.911A>T	p.Gln304Leu	missense_variant	6/89	ENST00000375735.7	NP_001368.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.911A>T	p.Gln304Leu	missense_variant	6/90		NM_001080463.2	ENSP00000497174.1
DYNC2H1	ENST00000375735.7	c.911A>T	p.Gln304Leu	missense_variant	6/89	1	NM_001377.3	ENSP00000364887.2

Frequencies

GnomAD3 genomes AF: 0.0448 AC: 6815 AN: 152128 Hom.: 210 Cov.: 32

Gnomad AFR AF: 0.0127

Gnomad AMI AF: 0.231

Gnomad AMR AF: 0.0566

Gnomad ASJ AF: 0.0649

Gnomad EAS AF: 0.00750

Gnomad SAS AF: 0.0532

Gnomad FIN AF: 0.0210

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0635

Gnomad OTH AF: 0.0641

GnomAD3 exomes AF: 0.0493 AC: 12272 AN: 249000 Hom.: 367 AF XY: 0.0520 AC XY: 7019 AN XY: 135096

Gnomad AFR exome AF: 0.0104

Gnomad AMR exome AF: 0.0440

Gnomad ASJ exome AF: 0.0718

Gnomad EAS exome AF: 0.00762

Gnomad SAS exome AF: 0.0515

Gnomad FIN exome AF: 0.0242

Gnomad NFE exome AF: 0.0644

Gnomad OTH exome AF: 0.0621

GnomAD4 exome AF: 0.0611 AC: 89308 AN: 1461022 Hom.: 2996 Cov.: 31 AF XY: 0.0611 AC XY: 44377 AN XY: 726782

Gnomad4 AFR exome AF: 0.0104

Gnomad4 AMR exome AF: 0.0470

Gnomad4 ASJ exome AF: 0.0694

Gnomad4 EAS exome AF: 0.00983

Gnomad4 SAS exome AF: 0.0523

Gnomad4 FIN exome AF: 0.0267

Gnomad4 NFE exome AF: 0.0674

Gnomad4 OTH exome AF: 0.0569

GnomAD4 genome AF: 0.0448 AC: 6817 AN: 152246 Hom.: 211 Cov.: 32 AF XY: 0.0443 AC XY: 3298 AN XY: 74444

Gnomad4 AFR AF: 0.0127

Gnomad4 AMR AF: 0.0564

Gnomad4 ASJ AF: 0.0649

Gnomad4 EAS AF: 0.00752

Gnomad4 SAS AF: 0.0541

Gnomad4 FIN AF: 0.0210

Gnomad4 NFE AF: 0.0635

Gnomad4 OTH AF: 0.0644

Alfa AF: 0.0598 Hom.: 233

Bravo AF: 0.0468

TwinsUK AF: 0.0588 AC: 218

ALSPAC AF: 0.0711 AC: 274

ESP6500AA AF: 0.0134 AC: 51

ESP6500EA AF: 0.0659 AC: 544

ExAC AF: 0.0498 AC: 6014

Asia WGS AF: 0.0200 AC: 69 AN: 3478

EpiCase AF: 0.0659

EpiControl AF: 0.0694

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 14, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Jeune thoracic dystrophy Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Asphyxiating thoracic dystrophy 3 Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 03, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	.;T;.;T;.;.
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	D;.;D;T;.;T
MetaRNN	Benign	0.0025	T;T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.1	.;M;M;M;M;M
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.5	.;D;D;.;.;D
REVEL	Benign	0.29
Sift	Benign	0.11	.;T;T;.;.;T
Sift4G	Benign	0.33	.;T;T;.;.;T
Polyphen		0.030, 1.0, 0.087	.;B;D;B;B;B
Vest4		0.56, 0.33, 0.56
MPC		0.063
ClinPred		0.031	T
GERP RS		5.0
Varity_R		0.21
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs12146610; hg19: chr11-102988504;